Alcohol dependence is a serious disorder for which effective treatments are lacking. Dysregulation of the serotonin system has been widely implicated in alcohol dependence though little is known about chronic ethanol's effects on serotonin neurons themselves or the microcircuit to which they belong. In the dorsal raphe (DR), a midbrain structure from which 50% of the brain's serotonin arises, serotonin neuron activity is modulated by local GABA neurons. The effects of chronic ethanol on GABA neurons of the DR and their modulation of serotonin neuron activity have not been explored to date. Using whole-cell slice electrophysiology, chronic ethanol vapor exposure, behavioral, optogenetic and chemogenetic approaches, the goal of this proposal is to test the hypothesis that chronic ethanol induces adaptations in GABA neuron function within the DR, resulting in altered modulation of serotonin neuron activity. The results of the proposed experiments will provide insight into the role of DR GABA neurons in dysregulated serotonin activity resulting from chronic ethanol exposure and will inform the development of pharmacotherapies targeting the serotonin system for the treatment of alcoholism.
Chronic alcohol use is a pervasive health concern that involves adaptations in both the serotonin and GABA systems of the brain. GABA modulates serotonin neuron activity in the dorsal raphe (DR), a major serotonergic nucleus of the mibrain. This proposal will use a mouse model of chronic ethanol exposure, whole-cell slice electrophysiology, optogenetic, chemicogenetic and behavioral approaches to explore the hypothesis that adaptations in DR GABA neuron function following chronic ethanol exposure leads to dysregulated serotonin neuron activity in the DR.
|Radke, Anna K; Jury, Nicholas J; Kocharian, Adrina et al. (2017) Chronic EtOH effects on putative measures of compulsive behavior in mice. Addict Biol 22:423-434|
|Rinker, Jennifer A; Marshall, S Alex; Mazzone, Christopher M et al. (2017) Extended Amygdala to Ventral Tegmental Area Corticotropin-Releasing Factor Circuit Controls Binge Ethanol Intake. Biol Psychiatry 81:930-940|
|Navarro, Montserrat; Olney, Jeffrey J; Burnham, Nathan W et al. (2016) Lateral Hypothalamus GABAergic Neurons Modulate Consummatory Behaviors Regardless of the Caloric Content or Biological Relevance of the Consumed Stimuli. Neuropsychopharmacology 41:1505-12|
|Charpentier, Thomas H; Waldo, Gary L; Lowery-Gionta, Emily G et al. (2016) Potent and Selective Peptide-based Inhibition of the G Protein G?q. J Biol Chem 291:25608-25616|
|Pleil, Kristen E; Lowery-Gionta, Emily G; Crowley, Nicole A et al. (2015) Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala. Neuropharmacology 99:735-49|
|Kash, Thomas L; Pleil, Kristen E; Marcinkiewcz, Catherine A et al. (2015) Neuropeptide regulation of signaling and behavior in the BNST. Mol Cells 38:1-13|
|Lowery-Gionta, Emily G; Marcinkiewcz, Catherine A; Kash, Thomas L (2015) Functional alterations in the dorsal raphe nucleus following acute and chronic ethanol exposure. Neuropsychopharmacology 40:590-600|